Antimicrobial innovation by Big Pharma has slowed to a crawl while an epidemic of antimicrobial-resistant infections surges, threatening the public health. The overarching goal of the Wisconsin Antimicrobial Drug Discovery and Development Center is to develop therapeutic countermeasures to tackle the antimicrobial resistance crisis. Based upon our preliminary data, we hypothesize that natural product exploration of symbiotic environments using complementary and integrated cutting-edge approaches will provide a new paradigm for antimicrobial drug discovery. The Center proposes innovative conceptual and technical advances to overcome critical bottlenecks identified in traditional antimicrobial drug discovery platforms to deliver therapeutic countermeasures for the drug-resistance epidemic.